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Sanford-Burnham researchers find drug that could reverse Alzheimer's


Orlando Sentinel

06-20-13

June 20--Scientists at Sanford-Burnham Medical Research Institute have discovered a combination of two FDA-approved drugs that appears to stop -- and possibly reverse -- the destructive changes in the brain caused by Alzheimer's disease.

By combining two widely used drugs, nitroglycerin and memantine, researchers created a third drug: NitroMemantine. In animal models, the hybrid appears to restore synapses -- the connections between neurons -- lost in the disease process, according to findings from a 10-year study published this week in the Proceedings of the National Academy of Sciences.

The new experimental drug may be the first to restore brain synapses lost during the progression of Alzheimer's disease, said Dr. Stuart Lipton, professor and director of Sanford-Burnham's neuroscience, aging and stem-cell research center, and the study's lead researcher.

"These findings actually mean that you might be able to intercede not only early but also a bit later," said Lipton, whose team studied the drug combination in mice and in brain cells derived from human stem cells.

The new combo drug -- developed by researchers at Sanford-Burnham's LaJolla, Calif., center -- is part of an overall effort focused at its Lake Nona sister facility that explores ways scientists can "re-purpose" already approved drugs in new ways to treat disease.

"The potential of drug re-purposing is enormous and will accelerate the pace of drug discovery," said Dr. Steve Gardell, senior director of scientific resources at Sanford-Burnham in Lake Nona.

To get a new drug approved for use in humans is a tremendous accomplishment, he said. Once a drug makes it that far, it should be leveraged for other uses.

Drugs are typically developed for one purpose; however, "observing how they act in humans can open our eyes to other, possibly more valuable, uses," Gardell said.

Alzheimer's disease progressively destroys the connections among neurons, leading to memory loss and cognitive decline.

In the United States, an estimated 5.4 million Americans have Alzheimer's, and as many as 16 million Americans will by 2050, according to the Alzheimer's Association.

In Florida, nearly half a million residents 65 or older already have Alzheimer's, according to the association.

The disease is characterized by abnormal clumps of proteins called amyloid plaques and tangled bundles of fibers.

Until now, medications have focused on attacking the plaques and tangles that form in the brain, said Lipton, who was part of the research team at Harvard that discovered how the drug memantine helped Alzheimer's patients.

That work contributed to the Food and Drug Administration approval of memantine -- sold as Namenda -- in 2003 for the treatment of Alzheimer's.

However, that drug's effectiveness has been limited.

The new research found that when nitroglycerin -- commonly used to treat chest pain or angina in patients with coronary heart disease -- was added to memantine to form a new drug, the results improved.

It took researchers 37 combinations of the drugs before they found one that worked, Lipton said.

"We show in this paper that memantine's ability to protect synapses is limited," Lipton said.

But working with mouse models of Alzheimer's disease, Lipton's team found NitroMemantine brought synapses back to normal within a few months and started to work within hours.

The study was funded by grants from agencies including the National Institutes of Health, the U.S. Department of Defense and the American Heart Association.

Calling the new research "very promising," Dr. David Smuckler, geriatrician and medical director of Orlando Health's Center for Aging and Memory Disorder Clinic, said he would welcome a new treatment.

"The medications we have now are not very good. A lot of patients don't respond, but they're the best we have," Smuckler said. "They don't do much to slow the process, and they definitely don't reverse it."

Dr. Gary Small, director of the Longevity Center at University of California Los Angeles and co-author of "The Alzheimer's Prevention Program," also said the research offered hope.

"I like the whole concept," Small said. "The anti-amyloid drugs have failed. This approach has some interesting science behind it."

The proof, both agree, remains to be seen when the drug is tested in humans.

That's the next step.

Once researchers find a pharmaceutical partner, the science will advance to human trials, said Lipton, who estimates it will be "several years" before it's on the market.

However, he is optimistic about the outcome.

"If you look at action of memantine in mice, it exactly tracks the results in humans. We have Namenda as a proof of principle that it works in humans," he said. "The fact that we have two safe drugs that are clinically tolerated makes the chance of success much higher.

"Most drugs fail in the brain not because they don't work, but because patients can't tolerate them," he said.

Lipton, also a practicing neurologist who sees Alzheimer's patients, said that although treatments thus far have been disappointing, he's optimistic that NitroMemantine will be more effective and "bring new hope to Alzheimer's patients."

mjameson@tribune.com or 407-420-5158

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